Several respiratory diseases and disorders could be better and more widely treated with an effective and low-cost biomimetic lung surfactant (LS) replacement. In present medical practice, LS replacements (used predominantly to treat neonatal respiratory distress syndrome) derive from animal lungs, are expensive, and carry risks of viral transmission and immune response. We propose to continue the development of a novel class of functional mimics of the lung surfactant proteins based on poly-N-substituted glycines (peptoids), which are sequence-specific heteropolymers synthesized on solid phase, similarly to peptides. Peptoids are protease resistant, and with proper sequence design can form stable, helical secondary structures that resist non-specific aggregation. Over the past 3.5 years, we have created and studied two different, novel classes of helical, amphipathic peptoid oligomers with sequence and structural similarity to (1) SP-B (residues 1-25) and (2) SP-C (residues 5-32). In vitro biophysical studies of the surface activities of these peptoid-based SP mimics in an LS-like lipid film demonstrate that the best designs within each class of mimics perform similarly to the natural peptides they are designed to replace. While initial results are very promising, much work remains to be done to develop peptoid-based SP mimics for a clinically useful, biomimetic LS replacement. We must now gain a deeper understanding of structure-activity relationships for the two classes of amphiphilic peptoid SP mimics under study. We propose to do this by varying key structural features and performing detailed studies of the effects on surface activity, in parallel with Molecular Dynamics simulations. For SP-C mimics, we will study the effects of hydrophobic helix length, side chain chemistry and overall helicity, and will also mimic the palmitoylation of natural SP-C. Proposed SP-B mimics will have increasingly protein-like sequences and side chain chemistries, and we will test the hypothesis that dimerization will improve their activity. We will carry out in vitro studies of peptoid-containing surfactant using CD, pulsating bubble surfactometry, a Langmuir trough/Wilhelmy surface balance, fluorescence microscopy, unilamellar vesicles, and X-ray reflectivity/diffraction to map out structure-activity relationships and study peptoid-lipid interactions. We will investigate surfactant formulations containing mimics of both SPs, and we will study the bicompatibility and in vivo efficacy of peptoid surfactants with lung epithelial cells and animal models of RDS.